To compare the importance of thromboxane A2 (TxA2) vs adenosine diphosphate (ADP) pathways of platelet recruitment we determined the relative anti-thrombotic and anti-hemostatic effects of clopidogrel (C), a selective ADP pathway antagonist, and aspirin (A), a TxA2 pathway antagonist, alone and in combination. We measured dose-response anti-thrombotic effects of clopidogrel and/or aspirin for metallic stents (MS), segments of prosthetic vascular graft or endarterectomized aorta interposed in exteriorized chronic AV femoral shunts in baboons. In addition, we assessed the corresponding anti-hemostatic effects on platelet aggregation, activation epitope expression, and template bleeding times (BTs). C decreased 111In-platelet and 125I-fibrin thrombotic accumulation in a dose-dependent manner (0.1-0.5 mg/kg/d), requiring 6 days of oral dosing to achieve maximal anti-thrombotic responses that plateaued at intermediate levels, i.e., C at 0.2 mg/kg/d decreased stent 111In-platelet deposition from 2.5q1.0 x109 to 0.79q0.32 x109 platelets (p=0.004), and eliminated ADP-induced platelet aggregation and ligand-induced binding site (LIBS) expression, while prolonging BTs from 3.3q0.8 min to 8.3q6.3 min (p<0.01). Platelet aggregation induced by collagen or TRAP was never fully inhibited despite dosing to 10 mg/kg/d. By contrast, A (1-10 mg/kg/d) did not decrease MS thrombosis, and minimally reduced platelet aggregation and LIBS expression induced by ADP and collagen, with BT prolonged from 3.3q0.8 min to 4.7q1.7 min (p<0.05). However, both anti-thrombotic and anti-hemostatic effects of C were substantially enhanced by the addition of A, i.e., C (0.2 mg/kg/d) plus A (1 mg/kg/d) decreased stent thrombosis from baseline of 2.5q1.0 x109 to 0.29q0.09 x109 platelets (p=0.002), compared with 0.79q0.32 x109 platelets for C alone (p=0.02). Thus, combining 0.2 mg/kg/d C and 1 mg/kg/d A produced maximal antithrombotic effects that were >additive, and prolonged BTs to 14.9q11.8 m in (p<0.01). Inhibitors of TxA2 greatly enhance the anti-thrombotic efficacy of ADP pathway antagonists while modestly impairing platelet hemostatic function. [unreadable] P51RR00165-36 1/1/96 - 12/31/96 Yerkes Regional Primate Research Center